Despite numerous advances in medical research, cancer remains the second leading cause of death in the United States. In the industrialized nations, roughly one in five persons will die of cancer. Traditional modes of clinical care, such as surgical resection, radiotherapy and chemotherapy, have a significant failure rate, especially for solid tumors. Failure occurs either because the initial tumor is unresponsive, or because of recurrence due to regrowth at the original site and/or metastases.
Lung cancer is one of the most common malignancies worldwide and is the second leading cause of cancer death in man. See, American Cancer Society, Cancer facts and figures, 1996, Atlanta. Approximately 178,100 new cases of lung cancer were to be diagnosed in 1997, accounting for 13% of cancer diagnoses. An estimated 160,400 deaths due to lung cancer would occur in 1997 accounting for 29% of all cancer deaths. The one-year survival rates for lung cancer have increased from 32% in 1973 to 41% in 1993, largely due to improvements in surgical techniques. The 5 year survival rate for all stages combined is only 14%. The survival rate is 48% for cases detected when the disease is still localized, but only 15% of lung cancers are discovered that early. Among various forms of lung cancer, non-small cell lung cancer (NSCLC) accounts for nearly 80% of all new lung cancer cases each year. For patients diagnosed with NSCLC, surgical resection offers the only chance of meaningful survival. On the other hand, small cell lung cancer is the most malignant and fastest growing form of lung cancer and accounts for the rest of approximately 20% of new cases of lung cancer. The primary tumor is generally responsive to chemotherapy, but is followed by wide-spread metastasis. The median survival time at diagnosis is approximately 1 year, with a 5 year survival rate of 5%.
In spite of major advances in cancer therapy including improvements in surgical resection, radiation treatment and chemotherapy, successful intervention for lung cancer in particular, relies on early detection of the cancerous cells. Neoplasia resulting in benign tumors may be completely cured by removing the mass surgically. If a tumor becomes malignant, as manifested by invasion of surrounding tissue, it becomes much more difficult to eradicate. Therefore, there remains a considerable need in the art for the development of methods for detecting the disease at the early stage. There also exits a pressing need in the art for developing diagnostic methods to monitor or prognose the progression of the disease as well as methods to treat various conditions. However, the vast variability in the nature of the disease has rendered the search for cellular markers, such as genes that are preferably overexpressed in primary lung cancer cells and useful for diagnostic and therapeutic methods, difficult.
Tumor often results from genetic alterations occurring spontaneously, or from viral infection, or in response to chemical carcinogens or radiation. Genes responsible for transforming a normal cell to a cancer (or neoplastic) cell are known as oncogenes. With the advent of recombinant DNA technology, a large number of oncogenes have been identified, cloned and sequenced. In most cases, the identified oncogenes are in fact altered form of one of the same native cellular genes, known as the proto-oncogenes. Related techniques have revealed that cell transformation can also be caused by overproduction of certain normal gene products. Overexpression of proto-oncogene may result from an amplification of the gene copies, or from a chromosomal rearrangement that has brought the proto-oncogene under the control of an inappropriate regulatory element, such as a constitutively activated promoter. The present invention provides the first identification of proto-oncogenes that are preferably overexpressed in primary lung cancer cells. In addition, the methods described herein provide a significant contribution to the area of lung cancer diagnosis, monitoring and treatment.